Frequently referred to as the ‘magic methyl effect’, the installation of methyl groups—especially adjacent (α) to heteroatoms—has been shown to dramatically increase the potency of biologically active molecules^1,2,3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings¹. Here we report a regioselective and chemoselective oxidative C(sp³)–H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C–H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF₃PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C–H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp³)–H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites—including drugs (for example, tedizolid) and natural products—are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates—an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1—via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.

通常被称为“神奇的甲基效应”，甲基基团的安装——尤其是与杂原子相邻的 (α)——已被证明可以显着提高生物活性分子^1,2,3的效力。然而，现有的甲基化方法显示范围有限，尚未在复杂环境中得到证实¹。在这里，我们报告了一种区域选择性和化学选择性氧化 C( sp ³ )-H 甲基化方法，该方法与药物支架和天然产物的后期功能化兼容。这结合了高度位点选择性和化学选择性的 C-H 羟基化与温和的、官能团耐受的甲基化。使用小分子锰催化剂，Mn(CF ₃PDP），在低负载（底物/催化剂比率为 200）下，在杂环核上提供靶向 C-H 羟基化，同时保留电子中性和富电子芳基。氟或路易斯酸辅助形成反应性亚胺或氧鎓中间体使得能够使用温和亲核的有机铝甲基化试剂，该试剂在基底上保留其他亲电子功能。我们展示了这个后期 C( sp ³)–H 甲基化在 41 个底物上，包含 16 个不同的药用重要核心，包括富电子芳基、杂环、羰基和胺。十八个具有竞争位点的药理学相关分子——包括药物（例如，泰地唑胺）和天然产物——在最富电子、空间位阻最小的位置选择性地甲基化。我们展示了两种神奇的甲基底物的合成——核受体 RORc 的反向激动剂和 1-磷酸鞘氨醇受体 1 的拮抗剂——通过药物或其晚期前体的晚期甲基化。我们还展示了阿比特龙类似物的 B 环碳环的远程甲基化。